1. Field of the Invention
The present invention relates to the fields of phosphatidylserine biology, and to treating tumors and viral infections. It provides surprising new constructs, compositions, methods and combinations for tumor vasculature targeting and cancer treatment, and for treating viral infections and other diseases. The invention particularly provides new phosphatidylserine binding constructs with surprising combinations of properties and diagnostic and therapeutic conjugates thereof. The new constructs effectively bind phosphatidylserine disease targets and enhancing their destruction, and can also deliver therapeutic agents to specific sites, and thus provide a range of methods for treating cancer, viral infections and other diseases.
2. Description of the Related Art
Tumor cell resistance to chemotherapeutic agents represents a significant problem in clinical oncology. Another major problem to address in tumor treatment is the desire for a “total cell kill”, i.e., killing all so-called “clonogenic” malignant cells that have the ability to grow uncontrolled and replace any tumor mass that might be removed by the therapy. Despite certain advances in the field, these are two of the main reasons why many prevalent forms of human cancer still resist effective chemotherapeutic intervention.
Due to the goal of developing treatments that approach a total cell kill, certain types of tumors have been more amenable to therapy than others. For example, the soft tissue tumors, e.g., lymphomas, and tumors of the blood and blood-forming organs, e.g., leukemias, have generally been more responsive to chemotherapeutic therapy than have solid tumors, such as carcinomas.
One reason for the susceptibility of soft and blood-based tumors to chemotherapy is the greater accessibility of lymphoma and leukemic cells to chemotherapeutic intervention. Simply put, it is much more difficult for most chemotherapeutic agents to reach all of the cells of a solid tumor mass than it is the soft tumors and blood-based tumors, and therefore much more difficult to achieve a total cell kill. Increasing the dose of chemotherapeutic agents most often results in toxic side effects, which generally limits the effectiveness of conventional anti-tumor agents.
Another tumor treatment strategy is the use of an “immunotoxin”, in which an anti-tumor cell antibody is used to deliver a toxin to the tumor cells. However, in common with chemotherapeutic approaches, immunotoxin therapy also suffers from significant drawbacks when applied to solid tumors. For example, antigen-negative or antigen-deficient cells can survive and repopulate the tumor or lead to further metastases. A further reason for solid tumor resistance to antibody-based therapies is that the tumor mass is generally impermeable to macromolecular agents such as antibodies and immunotoxins. Both the physical diffusion distances and the interstitial pressure within the tumor are significant limitations to this type of therapy.
An improved treatment strategy is to target the vasculature of solid tumors. Targeting the blood vessels of the tumors, rather than the tumor cells themselves, has certain advantages in that it is not likely to lead to the development of resistant tumor cells, and that the targeted cells are readily accessible. Moreover, destruction of the blood vessels leads to an amplification of the anti-tumor effect, as many tumor cells rely on a single vessel for their oxygen and nutrients. Exemplary vascular targeting agents (VTAs) are described in U.S. Pat. Nos. 5,855,866, 5,965,132, 6,261,535, 6,051,230 and 6,451,312, which describe the targeted delivery of anti-cellular agents and toxins to markers of tumor vasculature.
Another effective version of the vascular targeting approach is to target a coagulation factor to a marker expressed or adsorbed within the tumor vasculature or stroma (Huang et al., 1997; U.S. Pat. Nos. 6,093,399, 6,004,555, 5,877,289, and 6,036,955). The delivery of coagulants, rather than toxins, to tumor vasculature has the further advantages of reduced immunogenicity and even lower risk of toxic side effects. As disclosed in U.S. Pat. No. 5,877,289, a preferred coagulation factor for use in such tumor-specific “coaguligands” is a truncated version of the human coagulation-inducing protein, Tissue Factor (TF), the major initiator of blood coagulation.
More recently, phosphatidylserine (PS) was identified as a specific marker of tumor vasculature (Ran et al., 1998). This led to the development of new anti-PS immunoconjugates for delivering anti-cellular agents, toxins and coagulation factors to tumor blood vessels (U.S. Pat. Nos. 6,312,694, 6,783,760 and 6,818,213). In addition, it was discovered that unconjugated antibodies to PS exerted an anti-cancer effect without attachment to a therapeutic agent, which became known as the phosphatidylserine “naked antibody” approach to tumor vascular targeting and treatment (U.S. Pat. No. 6,406,693).
Although the foregoing methods have furthered the art of tumor treatment, the development of additional therapeutic and vascular targeting agents is needed to expand the number and effectiveness of therapeutic options. An important advance would be the identification of a group of therapeutic agents with anti-cancer properties and therapeutic effects in other systems, such as in treating viral infections. The generation of new targeted constructs that can be made from two human components, particularly those that do not rely on the use of antibodies for targeting, would be a significant development, providing improved safety. Designing and developing new agents that enhance a patients' own response against disease, i.e., that increase host effector functions, would be of great value in maximizing therapeutic responses, particularly where the same mechanisms could be leveraged against cancer and other diseases, such as viral infections and diseases.